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Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis.


ABSTRACT: Neutrophil chemotaxis plays an essential role in innate immunity, but the underlying cellular mechanism is still not fully characterized. Here, using a small-molecule functional screening, we identified NADPH oxidase-dependent reactive oxygen species as key regulators of neutrophil chemotactic migration. Neutrophils with pharmacologically inhibited oxidase, or isolated from chronic granulomatous disease (CGD) patients and mice, formed more frequent multiple pseudopodia and lost their directionality as they migrated up a chemoattractant concentration gradient. Knocking down NADPH oxidase in differentiated neutrophil-like HL60 cells also led to defective chemotaxis. Consistent with the in vitro results, adoptively transferred CGD murine neutrophils showed impaired in vivo recruitment to sites of inflammation. Together, these results present a physiological role for reactive oxygen species in regulating neutrophil functions and shed light on the pathogenesis of CGD.

SUBMITTER: Hattori H 

PROVIDER: S-EPMC2840460 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis.

Hattori Hidenori H   Subramanian Kulandayan K KK   Sakai Jiro J   Jia Yonghui Y   Li Yitang Y   Porter Timothy F TF   Loison Fabien F   Sarraj Bara B   Kasorn Anongnard A   Jo Hakryul H   Blanchard Catlyn C   Zirkle Dorothy D   McDonald Douglas D   Pai Sung-Yun SY   Serhan Charles N CN   Luo Hongbo R HR  

Proceedings of the National Academy of Sciences of the United States of America 20100208 8


Neutrophil chemotaxis plays an essential role in innate immunity, but the underlying cellular mechanism is still not fully characterized. Here, using a small-molecule functional screening, we identified NADPH oxidase-dependent reactive oxygen species as key regulators of neutrophil chemotactic migration. Neutrophils with pharmacologically inhibited oxidase, or isolated from chronic granulomatous disease (CGD) patients and mice, formed more frequent multiple pseudopodia and lost their directional  ...[more]

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